State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; School of Medicine, Chengdu University, Chengdu 610106, China.
Chin J Nat Med. 2020 Jul;18(7):517-525. doi: 10.1016/S1875-5364(20)30062-5.
Nagilactone E (NLE), a natural product with anticancer activities, is isolated from Podocarpus nagi. In this study, we reported that NLE increased programmed death ligand 1 (PD-L1) expressions at both protein and mRNA levels in human lung cancer cells, and enhanced its localization on the cell membrane. Mechanistically, NLE increased the phosphorylation and expression of c-Jun, and promoted the localization of c-Jun in the nucleus, while silencing of c-Jun by small interfering RNA (siRNA) reduced NLE-induced PD-L1. Further study showed that NLE activated the c-Jun N-terminal kinases (JNK), the upstream of c-Jun, and its inhibitor SP600125 reversed the NLE-increased PD-L1. Moreover, NLE-induced PD-L1 increased the binding intensity of PD-1 on the cell surface. In summary, NLE upregulates the expression of PD-L1 in lung cancer cells through the activation of JNK-c-Jun axis, which has the potential to combine with the PD-1/PD-L1 antibody therapies in lung cancer.
那格列酮 E（NLE）是一种具有抗癌活性的天然产物，从罗汉松中分离得到。在这项研究中，我们报道 NLE 可在蛋白和 mRNA 水平上增加人肺癌细胞中程序性死亡配体 1（PD-L1）的表达，并增强其在细胞膜上的定位。在机制上，NLE 增加了 c-Jun 的磷酸化和表达，并促进 c-Jun 定位于细胞核，而通过小干扰 RNA（siRNA）沉默 c-Jun 可减少 NLE 诱导的 PD-L1。进一步的研究表明，NLE 激活了 c-Jun N 端激酶（JNK），即 c-Jun 的上游激酶，其抑制剂 SP600125 逆转了 NLE 增加的 PD-L1。此外，NLE 诱导的 PD-L1 增加了 PD-1 在细胞表面的结合强度。总之，NLE 通过激活 JNK-c-Jun 轴上调肺癌细胞中 PD-L1 的表达，这有可能与肺癌中的 PD-1/PD-L1 抗体疗法相结合。
